Budesonide administered using chlorofluorocarbon and hydrofluoroalkane pressurized metered-dose inhalers: pharmacokinetics, pharmacodynamics and clinical equivalence.

OBJECTIVE: The traditional chlorofluorocarbon (CFC) propellants used in pressurized metered-dose inhalers (pMDIs) have unacceptable environmental effects and are being replaced by alternatives such as hydrofluoroalkanes (HFAs). However, there is a need to ensure that pMDIs with these novel propellants are as effective and safe as their older counterparts. MATERIALS AND METHODS: Single-dose pharmacokinetic and multiple high-dose Phase I studies in healthy volunteers and randomized, controlled 12-week Phase III clinical trials in children, adolescents and adults with mild-to-moderate asthma have been performed to compare the efficacy and safety of HFA-based budesonide inhaler therapy with the traditional CFC-based pMDI. RESULTS: The pharmacokinetic study in 40 persons showed comparable characteristics of CFC and HFApMDIs, with good dose-proportionality, at doses of 400, 800 and 1,600 microg. The high-dosage (1,600 microg/day) study in 48 subjects showed both inhaler types to be similar in terms of effects on hypothalamic-pituitary-adrenal axis function over 4 weeks. The pediatric clinical study involved 159 children and showed noninferiority of the HFA pMDI in terms of 12-week change in forced expiratory volume in 1 sec, other spirometric parameters and symptomatic measures. The adolescent/adult study in 321 subjects also showed similarity between the two formulations, in terms of 12-week primary endpoint (changes in morning peak expiratory flow rates) and other lung function and symptom measures. Both formulations were well-tolerated, with no safety issues being identified for the novel HFA inhaler in any study. CONCLUSION: Budesonide HFA pMDI is pharmacokinetically and clinically comparable to the traditional CFC-based inhaler, with similar safety profile.

Clinical comparability between the CFC and HFA budesonide pressurised metered-dose inhalers in paediatric patients with asthma: a randomised controlled trial.

OBJECTIVE: To evaluate the efficacy and tolerability of a novel hydrofluoroalkane (HFA) pressurised metered dose inhaler (pMDI) formulation of budesonide (Pulmicort) versus the conventional chlorofluorocarbon (CFC) pMDI formulation in paediatric patients with asthma. METHODS: This was a Phase III, multicentre, 12-week, double-blind, randomised, parallel-group study involving children (6-12 years of age) with mild to moderate asthma. Patients received either budesonide HFA pMDI or budesonide CFC pMDI 200 mug twice daily, with or without a spacer (NebuChamber/Nebunette). Primary efficacy endpoint: mean percentage change in forced expiratory volume in 1 second (FEV(1)) from baseline to week 12. Secondary efficacy endpoints included changes in FEV(1) per cent of predicted normal, forced vital capacity, morning and evening peak expiratory flow rate, asthma symptoms and use of rescue medication. RESULTS: A total of 159 patients received treatment (HFA 77, CFC 82). For mean percentage change in FEV(1) from baseline to week 12, the difference between the treatments (CFC pMDI - HFA pMDI) was -3.1% (95% confidence interval [CI] -8.0% to 1.8%) for the full analysis set and was not affected by spacer use. The upper CI was < 10% (the predefined non-inferiority margin), so non-inferiority was demonstrated. Improvements in the secondary efficacy endpoints with both budesonide formulations were not significantly different. In both groups there were similar numbers of adverse events and no evidence of oral candidiasis at week 12. CONCLUSIONS: Treatment with budesonide HFA pMDI is effective and well tolerated in children with asthma and is clinically comparable to budesonide CFC pMDI.

Effect of 1 year daily treatment with 400 microg budesonide (Pulmicort Turbuhaler) in newly diagnosed asthmatics.

The aim of this study was to investigate whether treatment with a low daily dose of 400 microg inhaled budesonide (Pulmicort Turbuhaler) in newly diagnosed asthmatics could influence the course of asthma. Seventy five adult patients, mostly with mild asthma, diagnosed during the previous year and bronchial hyperresponsiveness, participated in a double-blind, randomized, parallel-group multicentre study. They were treated with budesonide 200 microg b.i.d. or placebo, delivered via Turbuhaler for 12 months and followed-up for another 6 months without inhaled steroid treatment. Airway function, symptom scores, reactivity to histamine and inflammatory indices in blood were assessed. The mean increase in morning peak expiratory flow (PEF) was 28 L x min(-1) after budesonide treatment compared with no increase in the placebo group (p=0.011). The provocative dose of histamine causing a 20% fall in forced expiratory volume in one second (PD20) (geometric mean) increased in the budesonide group by approximately two doubling dose steps, but not in the placebo group (p=0.0003). The difference between groups with regard to improvement in asthma symptom scores and inflammatory indices did not reach statistical significance. During the 6 month follow-up, the PEF values of the patients who had previously been treated with budesonide decreased by 18 L x min(-1) while the PD20 decreased by approximately one doubling dose step. In conclusion, early treatment with a low dose of budesonide improves airway function and decreases bronchial responsiveness, but the improvements are short-lasting without continued treatment.